The present invention relates to new cyclic compounds having a cycloalkylene chain.
Hydroxy or alkoxy cyclopropane amides (WO 9209566, EP 436199, U.S. Pat. No. 5,459,150) and hydroxy or alkoxy cyclobutane amides (U.S. Pat. No. 5,187,192) are known from the prior art for use as 5-lipoxygenase inhibitors.
Other cyclopropane-amide or -thioamide compounds having an unsaturated chain are described as pesticides (EP 369762).
Cyclopropane-indole compounds for use in the treatment of neurodegenerative disorders (EP 568136) are also found.
Finally, some publications mention amide compounds having a cyclohexane chain as intermediates or synthesis products (Indian J. Chem., 1974, 12(7), pp. 664-7; Bull. Chem. Soc. Jap., 1968, 41(12), pp. 3008-11).
The compounds of the present invention are new and exhibit pharmacological characteristics that are very valuable in respect of melatoninergic receptors.
Numerous studies in the last ten years have demonstrated the key role of melatonin (N-acetyl-5-methoxytryptamine) in many physiopathological phenomena and in the control of the circadian rhythm. Its half-life is quite short, however, owing to the fact that it is rapidly metabolised. Great interest therefore lies in the possibility of providing the clinician with melatonin analogues that are metabolically more stable, have an agonist or antagonist character and may be expected to have a therapeutic effect that is superior to that of the hormone itself.
In addition to their beneficial action on circadian rhythm disorders (J. Neurosurg. 1985, 63, pp. 321-341) and sleep disorders (Psychopharmacology, 1990, 100, pp. 222-226), ligands of the melatoninergic system have valuable pharmacological properties in respect of the central nervous system, especially anxiolytic and antipsychotic properties (Neuropharmacology of Pineal Secretions, 1990, 8 (3-4), pp. 264-272) and analgesic properties (Pharmacopsychiat., 1987, 20, pp. 222-223), as well as for the treatment of Parkinson""s disease (J. Neurosurg. 1985, 63, pp. 321-341) and Alzheimer""s disease (Brain Research, 1990, 528, pp. 170-174). Those compounds have also demonstrated activity in relation to certain cancers (Melatoninxe2x80x94Clinical Perspectives, Oxford University Press, 1988, pp. 164-165), ovulation (Science 1987, 227, pp. 714-720), diabetes (Clinical Endocrinology, 1986, 24, pp. 359-364), and in the treatment of obesity (International Journal of Eating Disorders, 1996, 20 (4), pp. 443-446). Those various effects are exerted via the intermediary of specific melatonin receptors. Molecular biology studies have demonstrated the existence of a number of receptor sub-types that are capable of binding that hormone (Trends Pharmacol. Sci., 1995, 16, p. 50 WO 97.04094). It has been possible, for various species, including mammals, for some of those receptors to be located and characterised. In order to be able to understand the physiological functions of those receptors better, it is of great advantage to have available specific ligands. Moreover, such compounds, by interacting selectively with one or other of those receptors, may be excellent medicaments for the clinician in the treatment of pathologies associated with the melatoninergic system, some of which have been mentioned above.
The compounds of the present invention, in addition to being new, exhibit a very strong affinity for melatonin receptors and/or selectivity for one or other of the melatoninergic receptor sub-types.
The present invention relates more especially to compounds of formula (I): 
wherein
A represents:
a ring system of formula (II): 
wherein X and Y, which may be identical or different, represent an oxygen atom, a sulphur atom or a CH2 group,
D represents a benzene ring or a naphthalene,
and the symbol means that the bonds may be single or double, with the proviso that the valency of the atoms is respected,
wherein R substitutes either the ring system D or the ring containing X and Y, and G1 substitutes the ring containing X and Y,
or or a ring system of formula (III): 
wherein Z represents an oxygen atom, a sulphur atom, a CH2 group or an NR1 group (wherein R1 represents a hydrogen atom, a linear or branched (C1-C6)alkyl group, an aryl group or an aryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched),
Dxe2x80x2 represents a benzene ring or a pyridine ring, and the symbol is as defined hereinabove,
wherein R substitutes the Dxe2x80x2 ring and G1 substitutes the other ring, it being understood that the ring systems of formula (II) or (III) may be substituted, in addition to the R and G1 groups, by from one to three identical or different groups selected from Ra, ORa, hydroxyl, CORa, formyl, COORa, carboxyl and OCORa,
wherein Ra represents a substituted or unsubstituted linear or branched (C1-C6)alkyl group, a substituted or unsubstituted linear or branched (C2-C6)alkenyl group, a substituted or unsubstituted linear or branched (C2-C6)alkynyl group, a linear or branched polyhalo-(C1-C6)alkyl group, a substituted or unsubstituted (C3-C8)cycloalkyl group, a substituted or unsubstituted (C3-C8)cycloalkyl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, a substituted or unsubstituted (C3-C8)cycloalkenyl group, a substituted or unsubstituted (C3-C8)cycloalkenyl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, an aryl group, an aryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, a heteroaryl group or a heteroaryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched,
R represents a hydrogen or halogen atom, or a hydroxyl, SH, Ra, ORa or S(O)nRa group wherein n is 0, 1 or 2 and Ra is as defined hereinabove,
or forms, with the carbon atom carrying it and with an adjacent carbon atom, a ring of formula (IV): 
wherein E represents an oxygen atom or an xe2x80x94S(O)nxe2x80x94 group wherein n is as defined hereinabove,
wherein the resulting ring contains from 5 to 7 atoms, may contain one or more unsaturations and may be substituted by one or more groups selected from linear or branched (C1-C6)alkyl, linear or branched (C1-C6)alkoxy, carboxy, linear or branched (C1-C6)alkoxy-carbonyl, hydroxy and oxo,
G1 and G2, which may be identical or different, represent a single bond or an alkylene chain xe2x80x94(CH2)txe2x80x94(wherein t is 1, 2, 3 or 4), unsubstituted or substituted by one or more identical or different radicals selected from hydroxy, carboxy, formyl, Ra, ORa, COORa, CORa, (wherein Ra is as defined hereinabove) and halogen atoms,
p is 0,1, 2, 3 or 4,
q is 0,1, 2, 3 or 4,
with 1xe2x89xa7p+qxe2x89xa74,
B represents an xe2x80x94NR1aC(Q)R2a, xe2x80x94NR1aC(Q)NR2aR3a or xe2x80x94C(Q)NR1aR2a group wherein R1a, R2a and R3a, which may be identical or different, can have any of the values of Ra or may represent a hydrogen atom, and Q represents an oxygen or sulphur atom,
it being understood that:
the term xe2x80x9csubstitutedxe2x80x9d applied to the terms xe2x80x9calkylxe2x80x9d, xe2x80x9calkenylxe2x80x9d and xe2x80x9calkynylxe2x80x9d means that those groups are substituted by one or more identical or different radicals selected from hydroxy, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)alkyl, linear or branched polyhalo-(C1-C6)alkyl, amino and halogen atoms,
the term xe2x80x9csubstitutedxe2x80x9d applied to the terms xe2x80x9ccycloalkylxe2x80x9d, xe2x80x9ccycloalkylalkylxe2x80x9d, xe2x80x9ccycloalkenylxe2x80x9d and xe2x80x9ccycloalkenylalkylxe2x80x9d means that the cyclic moiety of those groups is substituted by one or more identical or different radicals selected from hydroxy, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)alkyl, linear or branched polyhalo-(C1-C6)alkyl, amino and halogen atoms,
xe2x80x9carylxe2x80x9d is understood to mean the groups phenyl, naphthyl or biphenyl, it being possible for those groups to be substituted by one or more identical or different radicals selected from hydroxy, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)alkyl, linear or branched polyhalo-(C1-C6)alkyl, cyano, carboxy, linear or branched (C1-C6)alkoxy carbonyl, nitro, amino and halogen atoms,
xe2x80x9cheteroarylxe2x80x9d is understood to mean any mono- or poly-cyclic aromatic group containing from 5 to 10 atoms and containing from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulphur, it being possible for those groups to be substituted by one or more identical or different radicals selected from hydroxy, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)alkyl, linear or branched polyhalo-(C1-C6)alkyl, cyano, carboxy, linear or branched (C1-C6)alkoxy-carbonyl, nitro, amino and halogen atoms,
with the proviso that:
when A represents a naphthalene group unsubstituted or substituted by one methoxy or one methyl group, G1 and G2 simultaneously represent a single bond, and B represents an 
xe2x80x83or NHCOMe group, it is not possible to have (q=0 and p=4) or (q=4 and p=0),
when G1 represents a single bond and p+q=1, A cannot represent a naphthalene group substituted by one or more halogen atoms,
when A represents an indole group substituted in the 2-position by the group 
xe2x80x83B cannot represent a urea group,
when A represents an indole group substituted in the 2-position by a carboxyl or alkoxycarbonyl group, p is 1 and q is 0 (or q is 1 and p is 0), and G1 represents a single bond, B cannot represent a CONHAr group wherein Ar represents an aryl group,
their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
Among the pharmaceutically acceptable acids there may be mentioned by way of non-limiting example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, methanesulphonic acid, camphoric acid, oxalic acid, etc.
Among the pharmaceutically acceptable bases there may be mentioned by way of non-limiting example sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc.
The preferred compounds of the invention are those wherein p+q=1.
The preferred R substituents are the groups Ra, ORa and SRa, more especially Ra and ORa wherein Ra more preferably represents a linear or branched (C1-C6)alkyl group, a (C3-C8)cycloalkyl group, a (C3-C8)cycloalkyl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, an aryl group or an aryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, phenyl or benzyl,
or those wherein R forms with the carbon atom carrying it and with an adjacent carbon atom a ring of formula (IV) wherein E represents, for example, 
xe2x80x83wherein Q represents a sulphur or oxygen atom.
The invention relates more preferably to compounds wherein R represents an ORa group.
More advantageously, the invention relates to compounds wherein A represents a ring system of formula (II) substituted in the 7-position by R and in the 1- or 2-position by G1, or a system of formula (III) substituted in the 5-position by R and in the 3-position by G1, A preferably being unsubstituted or substituted (as well as by the substituents R and G1) by a group in the 2- or 3-position (formula II) or in the 2-position (formula III), this group being most preferably an alkoxy group, an aryl group or an arylalkyl group.
The preferred G1 and G2 groups are the single bond or the CH2 group.
The invention relates more especially to compounds wherein B represents an xe2x80x94NHCORa or xe2x80x94CONHRa group.
More advantageously, the invention relates to compounds wherein A is substituted
by a group of formula (V): 
wherein n is 0 or 1 and Bxe2x80x2 represents an xe2x80x94NHCORa or xe2x80x94CONHRa group (wherein Ra, is as defined hereinabove),
by an alkoxy, alkylthio or alkyl group,
and optionally by an alkoxy, aryl or arylalkyl group.
Still more especially, the invention relates to:
naphthalene, chroman or benzochroman compounds substituted in the 1- or 2-position (formula 11) by a group of formula (V), in the 7-position (formula 11) by an Ra, ORa or SRa group, and optionally substituted in the 3-position (formula II) by an aryl or arylalkyl group or in the 2-position (formula II) by an alkoxy group,
or benzothiophene, benzofuran, indole or azaindole compounds substituted in the 3-position (formula III) by a group of formnula (V), in the 5-position (formula III) by an Ra, ORa or SRa group and optionally substituted in the 2-position (formula III) by an aryl or arylalkyl group.
Very advantageously, the invention relates to naphthalene compounds substituted in the 1-position by a group of formula (V), in the 7-position by an ORa group and optionally substituted in the 2-position by an ORa group or in the 3-position by an aryl or arylalkyl group.
The invention relates more especially to compounds of formula (I) which are
N-[2-(7-methoxy-1-naphthyl)-1-cyclopropyl]acetamide
N-[2-(7-methoxy-1-naphthyl)-1-cyclopropyl]propanamide
N-[2-(7-methoxy-1-naphthyl)-1-cyclopropyl]butanamide
N-[2-(7-methoxy-1-naphthyl)-1-cyclopropyl]cyclopropanecarboxamide
N-[2-(2,7-dimethoxy-1-naphthyl)-1-cyclopropyl]acetamide
N-[2-(2,7-dimethoxy-1-naphthyl)-1-cyclopropyl]propanamide
N-[2-(2,7-dimethoxy-1-naphthyl)-1-cyclopropyl]butanamide
N-[2-(2-methoxy-1-naphthyl)-1-cyclopropyl]acetamide
N-[2-(2-methoxy-1-naphthyl)-1-cyclopropyl]acetanamide
N-[2-(2-methoxy-1-naphthyl)-1-cyclopropylmethy]acetamide
N-[2-(2-methoxy-1-naphthyl)-1-cyclopropylmethyl]propanamide
N-[2-(2-methoxy-1-naphthyl)-1-cyclopropylmethyl]butanamide.
The preferred configuration of compounds of formula (I) is when xe2x80x94G1xe2x80x94Axe2x80x94R group and xe2x80x94G2xe2x80x94Bxe2x80x94 group are in the trans configuration.
The enantiomers, diastereoisomers and addition salts with a pharmaceutically acceptable acid or base of the preferred compounds of the invention are an integral part of the invention.
The invention relates also to a process for the preparation of compounds of formula (I) characterised in that there is used as starting material a compound of formula (VI): 
wherein R, A, G1, G2, p and q are as defined hereinabove,
which is subjected, after activation to the acid chloride or in the presence of a coupling agent, to the action of an amine HNR1aR2a, wherein R1a and R2a are as defined hereinabove to yield a compound of formula (I/a), a particular case of the compounds of formula (I): 
wherein R, A, G1, G2, R1a, R2a, p and q are as defined hereinabove,
which may be subjected to the action of a thionisation agent, such as Lawesson""s reagent, to obtain a compound of formula (I/b), a particular case of the compounds of formula (I), 
wherein R, A, G1, G2, R1a, R2a, p and q are as defined hereinabove,
or subjected, after conversion to the corresponding azide, to a Curtius rearrangement to yield, after hydrolysis, an amine of formula (VII): 
wherein R, A, G1, G2, p and q are as defined hereinabove,
which is either:
reacted with an acyl chloride ClCOR1a or the corresponding mixed or symmetric anhydride wherein R1a is as defined hereinabove to yield a compound of formula (I/c), a particular case of the compounds of formula (I): 
wherein R, A, G1, G2, R1a, p and q are as defined hereinabove, followed optionally by the action of a compound of formula (VIII):
Raxe2x80x94Jxe2x80x83xe2x80x83(VIII)
wherein Ra is as defined hereinabove and J represents a leaving group, such as a halogen atom or a tosyl group,
to yield a compound of formula (I/d), a particular case of the compounds of formula (I): 
wherein R, A, G1, G2, Ra, R1a, p and q are as defined hereinabove,
the totality of the compounds (I/c) and (I/d) constituting the compounds of formula (I/e), a particular case of the compounds of formula (I): 
wherein R, A, G1, G2, R1a, R2a, p and q are as defined hereinabove,
which compounds of formula (I/e) may be subjected to the action of a thionisation agent, such as Lawesson""s reagent, for example, to yield a compound of formula (I/f), a particular case of the compounds of formula (I): 
wherein R, A, G1, G2, R1a, R2a, p and q are as defined hereinabove,
or
subjected to the action of a compound of formula (IX):
Qxe2x95x90Cxe2x95x90Nxe2x80x94R1axe2x80x83xe2x80x83(IX)
wherein Q and R1a are as defined hereinabove,
followed optionally by the action of a compound of formula (VIII) to yield a compound of formula (I/g), a particular case of the compounds of formula (I): 
wherein R, A, G1, G2, R1a, R2a, R3a, Q, p and q are as defined hereinabove,
which compounds (I/a) to (I/g) constitute the totality of the compounds of formula (I) and may be purified according to a conventional separation technique, are converted, if desired, into their addition salts with a pharmaceutically acceptable acid or base, and optionally separated into their isomers according to a conventional separation technique.
The starting compounds (VI) are either commercial compounds or are readily accessible to the person skilled in the art by conventional chemical reactions or by chemical reactions described in the literature.
The compounds of the invention and pharmaceutical compositions containing them have proved to be useful in the treatment of disorders of the melatoninergic system.
Pharmacological study of the compounds of the invention has in fact demonstrated that they are atoxic, have a very high selective affinity for melatonin receptors and have substantial activity on the central nervous system and, in particular, therapeutic properties in respect of sleep disorders, anxiolytic, antipsychotic and analgesic properties, as well as properties in respect of microcirculation, have been found, enabling it to be established that the compounds of the invention are useful in the treatment of stress, sleep disorders, anxiety, seasonal affective disorder, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue due to jetlag, schizophrenia, panic attacks, melancholia, appetite disorders, obesity, insomnia, psychotic disorders, epilepsy, diabetes, Parkinson""s disease, senile dementia, various disorders associated with normal or pathological ageing, migraine, memory loss, Alzheimer""s disease, and in cerebral circulation disorders. In another field of activity, it appears that the compounds of the invention can be used in the treatment of sexual dysfunctions, have ovulation-inhibiting and immunomodulating properties and are capable of being used in the treatment of cancers.
The compounds will preferably be used in the treatment of seasonal affective disorder, sleep disorders, cardiovascular pathologies, insomnia and fatigue due to jetlag, appetite disorders and obesity.
For example, the compounds will be used in the treatment of seasonal affective disorder and sleep disorders.
The present invention relates also to pharmaceutical compositions containing at least one compound of formula (I) on its own or in combination with one or more pharmaceutically acceptable excipients.
Among the pharmaceutical compositions according to the invention there may be mentioned more especially those that are suitable for oral, parenteral, nasal, per- or transcutaneous, rectal, perlingual, ocular or respiratory administration and especially tablets or dragees, sublingual tablets, sachets, paquets, gelatin capsules, glossettes, lozenges, suppositories, creams, ointments, dermal gels, and drinkable or injectable ampoules.
The dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the therapeutic indication, or any associated treatments and ranges from 0.01 mg to 1 g per 24 hours in 1 or more administrations.
The following Examples illustrate the invention and do not limit it in any way. The following Preparations yield synthesis intermediates for use in the preparation of the compounds of the invention.
Step A: (7-Methoxy-1-naphthyl)methyl Acetate
In a 2 liter flask, 48.6 g (0.225 mol) of [7-methoxy(naphth-1-yl)]acetic acid are dissolved in a mixture of 700 ml benzene/300 ml acetic acid and refluxed under argon in order to degas the mixture. 100 g (1 eq) of lead tetraacetate are added at room temperature. The reaction mixture is heated at 60-70xc2x0 C., at which temperature there is strong evolution of gas (release of CO2), followed by 30 minutes"" at boiling temperature. The reaction mixture is concentrated in vacuo and taken up while hot in CH2Cl2 (200 ml); 500 ml of ether are added slowly with stirring. The substantial amount of creamy white precipitate which forms is filtered off over Celite and rinsed with ether. The ethereal phase is then rendered basic by means of an ice-cold solution of 5% sodium hydrogen carbonate, neutralised with water, dried over Na2SO4 and concentrated under reduced pressure to yield an oil which recrystallises slowly when cold.
Step B: (7-Methoxy-1-naphthyl)methanol
34.5 g (0.15 mol) of the compound obtained in Step A are dissolved in 300 ml of methanol. 35 g (4 eq) of potassium hydroxide dissolved in 35 ml of water are added with vigorous stirring. After 3 hours at room temperature, the reaction mixture is hydrolysed over a mixture of ice/concentrated hydrochloric acid. The creamy white precipitate which forms is filtered off, washed several times with ice-cold water and dried over P2O5 using a dessicator. The title alcohol is recrystallised from a mixture of CH2Cl2/cyclohexane to yield white needles.
Step C: 7-Methoxy-1-naphthaldehyde
19.2 g (0.1 mol) of the compound obtained in Step B are dissolved in 300 ml of CH2Cl2. Under argon, 65 g (7.5 eq) of manganese oxide are added in three stages (txe2x95x900: 25 g, t=3 h :25 g, and t=24 h: 15 g). The alcohol is totally oxidised after a further 24 hours. The mixture is then filtered over Celite in order to remove the mineral compounds, rinsed with CH2Cl2 and then filtered over silica to yield an oil which solidifies on cooling.
Step D: Ethyl 3-(7-methoxy-1-naphthyl)-2-propenoate
2 g (10.7 mmol) of the compound obtained in Step C in 20 ml of anhydrous THF are placed in the presence of 515 mg (1.2 eq) of NaH (60% in oil) in 25 ml of anhydrous THF and 2.5 ml (1.2 eq) of triethyl phosphonoacetate. 3 hours"" stirring at room temperature and gentle refluxing overnight yield a dark-coloured oil.
Step E: 3-(7-Methoxy-1-naphthyl)-2-propenoic Acid
8.4 g (32.8 mmol) of the ester obtained in Step D dissolved in 150 ml of ethanol in the presence of 40 ml of 2N sodium hydroxide solution are stirred for 3 hours at room temperature and overnight at reflux to yield the title acid in the form of a white solid.
Step F: N-Methoxy-N-methyl-3-(7-methoxy-1-naphthyl)-2-propenamide
The acid chloride obtained starting from 6.5 g (28.5 mmol) of the acid obtained in Step E and 5 ml of oxalyl chloride are added dropwise to a suspension of N,O-dimethylhydroxylamine chloride (5.6 g) in a mixture of CH2Cl2/H2O in the presence of 3 g of Na2CO3. The protected acid is obtained in the form of a pale yellow solid.
Step G: Trans-N-methoxy-N-methyl-2-(7-methoxy-1-naphthyl)-1-cyclopropanecarboxamide
5.8 g (21.4 mmol) of the compound obtained in Step F dissolved in 30 ml of DMSO are added to a suspension of ylid produced starting from 10.6 g (2 eq) of Me3SOI dissolved while hot in 50 ml of DMSO and 1.25 g of NaH. After 15 hours"" stirring at room temperature and 4 hours at 50xc2x0 C., the title cyclopropane amide is obtained in the form of a brown oil.
Step H: Trans-2-(7-methoxy-1-naphthyl)-1-cyclopropanecarboxylic Acid
6 g (21 mmol) of the compound obtained in Step G in 50 ml of anhydrous ether and 15.4 g of potassium tert-butylate are stirred for 2 days at room temperature. 3.2 g of a light brown solid are collected and reacted without purification.
Step I: Trans-2-(7-methoxy-1-naphthyl)-1-cyclopropanamine
1.5 g (6.2 mmol) of the acid obtained in Step H and 770 xcexcl (1.3 eq) of ethyl chloroformate in the presence of triethylamine in acetone yield the mixed anhydride which is then treated with 550 mg (1.3 eq) of sodium azide. The acyl azide is then subjected to a rearrangement in 40 ml of anhydrous toluene at 80xc2x0 C. to yield the isocyanate. The isocyanate is stirred for 36 hours at room temperature in an aqueous solution of 20% hydrochloric acid to yield the title amine.
The following Preparations are obtained by the same procedure:
Step A: 3-(2-Methoxy-1-naphthyl)-2-propenenitrile
Starting from 5 g (26.85 mmol) of 2-methoxynaphthaldehyde in 30 ml of anhydrous THF in the presence of 1.3 g (1.2 eq) of NaH (60% in oil) in 15 ml of anhydrous THF and 6.5 ml (1.2 eq) of diethyl cyanomethylphosphonate, the title product is obtained in the form of a white solid.
Step B: Trans-2-(2-methoxy-1-naphthyl)-1-cyclopropanecarbonitrile
5 g (23.9 mmol) of the compound obtained in Step A dissolved in 50 ml of DMSO are added dropwise to the ylid formed starting from 7.9 g (1.5 eq) of trimethylsulphoxonium iodide and 1.15 g (1.2 eq) of NaH (60% suspension in oil) in 20 ml of DMSO. The title compound is obtained in the form of an oil and is purified by chromatography over silica gel (eluant: CH2Cl2/i-PrOH 98/2).
The following Preparations are obtained by the same procedure:
A solution of 0.1 mol of cyclobutenone in 50 ml of THF is added dropwise to the Grignard reagent formed starting from 1-bromo-2-methoxynaphthalene (0.1 mol) and 2.5 g of magnesium in 200 ml of THF. The reaction mixture is stirred. At the end of the reaction, the mixture is quenched with 3N HCl and stirred for 1 hour after dilution in 200 ml of ether. Following extraction with ether and concentration in vacuo of the organic phase, the corresponding cyclobutanone is obtained and is redissolved with hydroxylamine. After the oxime has formed, the mixture is subjected to hydrogenation over Raney nickel to yield the title amine.
Preparations 28 and 29 are obtained by following the procedure described in Preparation 27, starting from the appropriate substrates.
The procedure is as for Preparation 1, Steps D-I starting from 2-(7-methoxy-1-naphthyl)acetaldehyde.
The procedure is as for Preparation 17 starting from 2-(7-methoxy-3-phenyl)-acetaldehyde.
Step A: 2-(8,9-Dihydro-7H-furo[3,2-f]chromen-1-ylmethyl)cyclopropanecarbonitrile
The procedure is as for Preparation 17 starting from 2-(8,9-dihydro-7H-furo[3,2-f]-chromen-1-yl)acetaldehyde.
Step B:
The compound obtained in Step A is hydrolysed in an acidic or basic medium.
Preparations 33 and 34 are obtained by proceeding as in Preparation 32.